1. Field of the Invention
Drug-resistant microorganisms pose a serious threat to effective clinical management of infectious diseases. It is well-settled that microorganism drug-resistance is afforded by both extrachromosomal resistance determinants and random mutation of the cells; in the presence of the drug, these provide a selection advantage for the survival of the resistant bacteria. While mechanisms of drug-resistance vary, and in many instances are poorly understood, it is believed that for many drugs, including tetracycline, resistance is a function of cellular membrane efflux of the drug controlled by genetic information encoded in extrachromosomal plasmids. The resistance trait can be transmitted from resistant to sensitive organisms by transferal of the genetic material itself via resistance transfer factors carried by the cell. It is this genetically-mediated transfer of bacterial drug resistance traits which presents the most serious clinical implications, particularly when multiple-drug resistance is involved.
2. Discussion of Related Art
The clinical treatment of infectious diseases has thus been often designed to obviate the development of a drug-resistant microorganism population insofar as possible. In particular, combinations of antibiotics are often favored in antibiotic therapy to suppress the emergence of mutants expressing resistance to an individual drug employed in the therapy, particularly in the treatment of infectious diseases caused by microorganisms which tend rapidly to mutate to resistant strains. While synergistic effects have been reported for some of these combinations, the thrust of this therapy has been to treat the infection with minimum inhibitory concentrations (MIC) of one or more antibiotics to inhibit the growth of the infecting bacteria, including singly drug-resistant mutant strains, and increase the spectrum of sensitive microorganisms targeted by the drugs. While this approach is relatively successful in combating drug-resistant populations arising from random mutations, it is of little effect in the treatment of microorganisms with constitutive resistance (i.e., those carrying extrachromosomal resistance determinants) to one or more therapeutic drugs of first choice Accordingly, the infecting resistant microorganisms are treated with drugs which are of less clinical value, usually owing to their association with adverse side effects at effective dosage levels. In particular, diseases caused by microorganisms containing tetracycline resistance determinants are commonly managed by treatment of the host with a drug of lesser choice, frequently an aminoglycoside antibiotic; at the antibiotic dosages typically employed, however, aminoglycoside and nephro- toxicity are serious and not uncommon clinical problems. It is thus desirable to improve such alternative therapy to decrease risk of toxicity while maintaining or improving efficacy.